Candida species are the most common fungal pathogens of humans and the causative agents of oral, gastrointestinal and vaginal candidiasis, giving rise to severe morbidity in millions of individuals worldwide. Vaginal candidiasis affects ˜75% of women at least once during fertile age, equating to ˜30 million infection episodes/year (3× more than tuberculosis and 8× more than HIV: WHO 2007). Candida infections are also the 3rd most common hospital-acquired bloodstream infection, making Candida species more medically-important than most bacterial infections including Enterococci (E. coli) and Pseudomonas spp. Systemic candidiasis is fatal (30-50% mortality) with 300,000 cases/year of candidaemia, equating to 100,000 deaths/year. Furthermore, Candida infections are the most common oral manifestation of HIV infection, with 50% of HIV+ patients and 90% AIDS patients suffering from oral candidiasis. With ˜4 million cases of HIV/year, this equates to ˜2 million oral candidiasis cases/year. Indeed, one of the biggest killers of the immunocompromised population is fungal infection. In the USA, yearly healthcare costs for fungal infections are $2.6 billion, of which Candida infections account for $1.8 billion. EU healthcare costs are estimated to be similar. Therefore, Candida pathogens carry an immense health burden and represent a major socio-economic challenge for worldwide communities.
Candida albicans is a member of the normal human microbiome. Although typically a commensal of the oral cavity, gastrointestinal and urinogenitary tracts, C. albicans is also an extremely frequent cause of superficial infections such as vaginitis. Moreover, common iatrogenic procedures, such as gastrointestinal surgery, implantation of a central venous catheter or antibiotic treatment are major risk factors for disseminated candidiasis. This form of systemic candidiasis is now the third most common cause of nosocomial bloodstream infections and the mortality of severe sepsis caused by Candida species is over 50% in some patient groups.
Identifying new epithelial and fungal targets that stimulate protective host immunity will ultimately have major implications for global health.
C. albicans virulence relies on a number of factors, including morphological plasticity, the expression of adhesins and invasins, robust stress responses, immune evasion, metabolic flexibility and nutrient acquisition. However, it remains unclear, how C. albicans causes damage.
The mechanisms by which C. albicans damages host cells have been considered to be multi-factorial, and presumed to rely on a combination of adhesion, invasion, hyphal extension, turgor pressure and the secretion of hydrolytic enzymes. Although toxin production by C. albicans has long been postulated and the culture supernatants of C. albicans hyphae shown to exhibit haemolytic activity, the mechanism underlying C. albicans ability to lyse host cells has remained elusive. It is clear, however, that hyphae are essential for adhesion, invasion and damage. Thus, damage is caused by hyphae and/or a hyphal associated factor.
The gene ECE1 (extent of cell elongation 1) was first identified two decades ago due to its heightened expression during hypha formation. However, deletion of ECE1 did not affect hypha formation in C. albicans and phenotypic differences between C. albicans wild type and ECE1 deletion strains have not been reported. Despite this, ECE1 expression has been used as a marker for hypha formation in multiple independent studies and ECE1 is one of the most strongly expressed genes during hyphal formation. In fact, ECE1 is within a small group of core hyphal associated genes. It has previously been reported that recombinant Ece1 is processed by the protease, Kex2, at lysine/arginine residues. However, the function of Ece1 has never been shown.
Currently, the gold standard for treating fungal infections is the use of antifungal drugs, which predominantly target either the cell wall (echinocandins), cell membrane (polyenes) or ergosterol synthesis (azoles). However, the continuing increase in Candida infections together with increasing drug resistance highlights the need to discover new and better agents that target either (i) epithelial processes that recognise and normally restrict these potentially life-threatening pathogens to mucosal surfaces or (ii) fungal determinants that promote infection and/or mediate immune activation and protective immunity. Despite this, there are no vaccine candidates or immune-based intervention strategies for combating Candida infections. Likewise, there are no commercial drugs that specifically target mucosal fungal infections.